Biology:TIMM8A

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Short description: Protein-coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Mitochondrial import inner membrane translocase subunit Tim8 A, also known as deafness-dystonia peptide or protein is an enzyme that in humans is encoded by the TIMM8A gene.[1][2][3] This translocase has similarity to yeast mitochondrial proteins that are involved in the import of metabolite transporters from the cytoplasm into the mitochondrial inner membrane. The gene is mutated in deafness-dystonia syndrome (or Mohr-Tranebjaerg syndrome; MTS/DFN-1) and it is postulated that MTS/DFN-1 is a mitochondrial disease caused by a defective mitochondrial protein import system.[3]

Structure

The TIMM8A gene is located on q arm of chromosome X in position 22.1 and spans 3,313 base pairs.[4] The gene produces an 11 kDa protein composed of 97 amino acids.[5][6] The structure shows resemblance to yeast translocase of the inner membrane (TIM) proteins with two conserved paired cysteine residue motifs.[7] The cysteine residues organize zinc ions for stability and control other interactions with proteins.[7]

Function

The human TIMM8A gene codes for a translocase involved in the import and insertion of hydrophobic membrane proteins from the cytoplasm into the mitochondrial inner membrane.[4] It is also required for the transfer of beta-barrel precursors from the TOM complex to the sorting and assembly machinery (SAM complex) of the outer membrane. It acts as a chaperone-like protein that protects the hydrophobic precursors from aggregation and guide them through the mitochondrial intermembrane space. The TIMM8-TIMM13 complex mediates the import of proteins such as TIMM23, SLC25A12/ARALAR1 and SLC25A13/ARALAR2, while the predominant TIMM9-TIMM10 70 kDa complex mediates the import of much more proteins. TIMM8A has been implicated as a required element in normal neurologic development.[8]

Clinical significance

Mutation of TIMM8A is associated with Mohr-Tranebjaerg syndrome or deafness-dystonia syndrome, a mitochondrial disease postulated to be associated with a defective mitochondrial protein import system. [3]Mohr-Tranebjaerg syndrome is a recessive, X-linked neurodegenerative syndrome characterized by early-onset deafness followed by progressive dystonia in adulthood, progressive sensorineural hearing loss, mental retardation, dysphagia, paranoia, and optic atrophy.[9][10] It is known to be caused by a truncation or deletion of the 11 kDa protein product of TIMM8A.[11] Defects in this gene also cause Jensen syndrome, an X-linked disease with opticoacoustic nerve atrophy and muscle weakness.[4]

A 39-year-old Japanese male patient with a nonsense mutation of the CGA codon 80 of exon 2 by TGA in the TIMM8A gene was diagnosed with deafness-dystonia syndrome. Signs and symptoms included sensorineural deafness, dystonia, blepharospasm, brisk deep tendon reflexes and personality changes. However, there were no visual or sensory disturbances. The mother was found to be a heterozygous carrier for the mutation.[9] Another patient, an 11-year-old Dutch child with a de novo missense mutation (C66W; c.233C > G) in the TIMM8A gene, was diagnosed with sensorineural hearing impairment associated with Deafness-dystonia syndrome. Signs and symptoms included hyperreflexia, dyspraxia, synkinesis, atrophy, and progressive dystonia.[12] A third patient, a 30-year-old male with Deafness-dystonia syndrome, was found to have a novel 108delG mutation in the TIMM8A gene. Signs and symptoms were generalized dystonia, scoliosis, blepharospasm, and involuntary movements of the head and neck.[13] There are many more cases of mutations in the TIMM8A gene with varying symptoms, commonly including dystonia, mental deficiency, sensorineural hearing loss, optic atrophy, and others.[14][15][16][17][18]

Interactions

TIMM8A has been shown to interact with Signal transducing adaptor molecule[7] and TIMM13.[19][20] Three copies of TIMM8A and three copies of TIMM13 assemble to form a 70 kDa TIMM8-TIMM13 Complex with heterohexamer structure in the intermembrane space.[20][8] The TIMM8-TIMM13 Complex associates with the TIM22 complex whose core is composed of TIMM22 to import and assemble inner membrane proteins.[8]

References

  1. ↑ "The human family of Deafness/Dystonia peptide (DDP) related mitochondrial import proteins". Genomics 61 (3): 259–67. November 1999. doi:10.1006/geno.1999.5966. PMID 10552927. 
  2. ↑ "A novel X-linked gene, DDP, shows mutations in families with deafness (DFN-1), dystonia, mental deficiency and optic atrophy". Nature Genetics 14 (2): 177–80. October 1996. doi:10.1038/ng1096-177. PMID 8841189. 
  3. ↑ 3.0 3.1 3.2 "Entrez Gene: TIMM8A translocase of inner mitochondrial membrane 8 homolog A (yeast)". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=1678. 
  4. ↑ 4.0 4.1 4.2 "Entrez Gene: TIMM8A translocase of inner mitochondrial membrane 8A". https://www.ncbi.nlm.nih.gov/gene/1678. 
  5. ↑ "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. October 2013. doi:10.1161/CIRCRESAHA.113.301151. PMID 23965338. 
  6. ↑ "TIMM8A - Mitochondrial import inner membrane translocase subunit Tim8 A". https://amino.heartproteome.org/web/protein/O60220. 
  7. ↑ 7.0 7.1 7.2 "Interaction of the deafness-dystonia protein DDP/TIMM8a with the signal transduction adaptor molecule STAM1". Biochemical and Biophysical Research Communications 305 (2): 345–52. May 2003. doi:10.1016/S0006-291X(03)00767-8. PMID 12745081. Bibcode: 2003BBRC..305..345B. 
  8. ↑ 8.0 8.1 8.2 "TIMM8A - translocase of inner mitochondrial membrane 8A, mitochondrial". The UniProt Consortium. https://www.uniprot.org/uniprot/O60220. 
  9. ↑ 9.0 9.1 "A family with X-linked dystonia-deafness syndrome with a novel mutation of the DDP gene". Archives of Neurology 58 (6): 1004–7. June 2001. doi:10.1001/archneur.58.6.1004. PMID 11405816. 
  10. ↑ "The mitochondrial TIM22 preprotein translocase is highly conserved throughout the eukaryotic kingdom". FEBS Letters 464 (1–2): 41–7. December 1999. doi:10.1016/S0014-5793(99)01665-8. PMID 10611480. Bibcode: 1999FEBSL.464...41B. 
  11. ↑ "Human deafness dystonia syndrome is a mitochondrial disease". Proceedings of the National Academy of Sciences of the United States of America 96 (5): 2141–6. March 1999. doi:10.1073/pnas.96.5.2141. PMID 10051608. Bibcode: 1999PNAS...96.2141K. 
  12. ↑ "A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness-dystonia-optic atrophy syndrome". European Journal of Human Genetics 8 (6): 464–7. June 2000. doi:10.1038/sj.ejhg.5200483. PMID 10878669. 
  13. ↑ "A novel deafness/dystonia peptide gene mutation that causes dystonia in female carriers of Mohr-Tranebjaerg syndrome". Annals of Neurology 50 (4): 537–40. October 2001. doi:10.1002/ana.1160. PMID 11601506. 
  14. ↑ "Long-Term Follow-Up with Video of a Patient with Deafness-Dystonia Syndrome Treated with DBS-GPi". Stereotactic and Functional Neurosurgery 94 (2): 123–5. 2016. doi:10.1159/000445078. PMID 27100856. 
  15. ↑ "Xq22.1 contiguous gene deletion syndrome of X-linked agammaglobulinemia and Mohr-Tranebjærg syndrome". Annals of Allergy, Asthma & Immunology 116 (6): 578–9. June 2016. doi:10.1016/j.anai.2016.03.014. PMID 27048950. 
  16. ↑ "A Spanish sporadic case of deafness-dystonia (Mohr-Tranebjaerg) syndrome with a novel mutation in the gene encoding TIMM8a, a component of the mitochondrial protein translocase complexes". Neuromuscular Disorders 18 (12): 979–81. December 2008. doi:10.1016/j.nmd.2008.09.009. PMID 18952432. 
  17. ↑ "A novel mutation in the gene encoding TIMM8a, a component of the mitochondrial protein translocase complexes, in a Spanish familial case of deafness-dystonia (Mohr-Tranebjaerg) syndrome". American Journal of Medical Genetics. Part A 140 (4): 392–7. February 2006. doi:10.1002/ajmg.a.31079. PMID 16411215. 
  18. ↑ "Dystonia in the Mohr-Tranebjaerg syndrome responds to GABAergic substances". Movement Disorders 19 (10): 1241–3. October 2004. doi:10.1002/mds.20150. PMID 15390009. 
  19. ↑ "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology 3 (1). 2007. doi:10.1038/msb4100134. PMID 17353931. 
  20. ↑ 20.0 20.1 "Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex". Human Molecular Genetics 11 (5): 477–86. March 2002. doi:10.1093/hmg/11.5.477. PMID 11875042. 

Further reading



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